Volume 3a, Modern Aging Research
Intervention In the Aging Process, Part A: Quantitation, Epidemiology, and Clinical Research
Editors: William Regelson, F. Marott Sinex
1983, Alan R. Liss, Inc, New York
Magnesium (Mg) is important in many reactions, and in prevention and treatment of functional and structural disorders of many tissues and systems. There are numerous recent publications on its effects on enzymes, in subcellular and cellular preparations, and in plants and animals, including man. However, relatively little has been done on Mg in aging. It is necessary to draw largely from studies that show changes in Mg deficiency that resemble those of old age, and relate Mg requirements to deficiencies of other nutrients particularly those with which Mg interacts. It has been postulated that Mg deficiency early in life gives rise to chronic abnormalities that persist throughout life, increasing morbidity and mortality and shortening life (Seelig, 1977; 1977/1982; 1978; 1980). Little attention has been paid to special Mg needs of old people, to whether Mg inadequacy might contribute to the aging process, or to whether Mg supplementation might have any beneficial effects in the aged.
The general assumption that most Western diets are adequate in Mg has been questioned since analysis of metabolic balance studies disclosed that at intakes below 5 and 6 mg/kg/day in young women and men respectively, maintenance of Mg equilibrium is not consistent (Seelig, 1964). Analysis of numerous typical sample meals of Americans of all ages has shown that the Mg intakes are usually below the Recommended Dietary Allowance (RDA) (U.S. Dept. Agr. 1980). The RDI for Mg has been estimated at 300-350 mg/day for young women and young men, (Food and Nutr. Board, 1980), providing about 4.5-5 mg/kg/day. The RDAs may not be optimal for everyday living. especially for the elderly, since they are derived from balance studies with young healthy adults under controlled stable conditions — usually protected from the vicissitudes of life (Seelig, 1981). Studies to assess the influence of age: (psycho-social, physical, chronic disease and therapy) on the Mg needs have not been done. It is probable that Mg requirements are elevated in the elderly, in view of the many factors in old age that increase nutritional needs and interfere with utilization (Figure 1).
The Mg intake of old people tends to be low (U.S. Dept. Agr.,
1980; Vir & Love, 1979), and their intestinal absorption of
Mg declines gradually with increasing age (Mountokalakis et al,
1976); Johansson, 1979). Lower urinary Mg excretion has been
reported by old than by young men. (Simpson et al, 1978). Young
women excreted less Mg than did post menopausal women, a
difference that was more marked in those taking oral
contraceptives (Table 1, Goulding & McChesney, 1977).
Serum Mg levels have been reported as quite constant in healthy adults, regardless of age (Keating et al, 1969), and as lower in old than young adults (Henrotte et al, 1976/1980). In a study of circadian changes in serum Mg, young man exhibited lower peak (morning) levels than did old men (Touitou et al, 1978). All subjects had their lowest serum Mg levels during sleep hours at night. The greatest circadian amplitude was in old men. In an on-going study of chronically hospitalized patients, most of whom are old, low Mg levels and high Mg retention after parenteral loading are being encountered (Seelig & Berger, unpublished).
Increased estrogen levels, or administration of estrogen, caused both reduced serum levels and urinary output of Mg (Goldsmith et al, 1970; Goldsmith & Johnston, 1976/1981). These effects are attributed to estrogen-induced Mg shift to tissues. The bone loss of post-menopausal women has been correlated with the loss of bone matrix Mg, as well as of calcium (Ca); the higher incidence of thrombotic events in young .women and the increased incidence of cardiovascular disease in old women might be due to the shift of Mg from blood plasma in young and the loss of cardiac Mg in old woman (Goldsmith & Goldsmith, 1966; Goldsmith & Johnston, 1976/1980; Seelig, 1980).
Mg is predominantly an intracellular cation, and serum levels are an unreliable index of its status in the body (Walser, 1967; Seelig, 1980; Wacker, 1980). Cardiac integrity being particularly vulnerable to Mg loss (Seelig, 1972; Seelig & Heggtveit, 1974), the drop in myocardial Mg seen in aging rats may be germane to the high cardiac disease rates in the aged. There were striking reductions in myocardial Mg levels of old versus young female rats. The septum and ventricles of male rats lost the most Mg with increasing age (Figure 2). The Mg reduction was accompanied by lesser falls in Ca and potassium (K), but not in phosphate (P) levels. The cation changes ware not related to dilutional factors, as the oldest rat. had the lowest tissue water levels. There were significantly lower Mg levels in aorta and liver of old rats than in young, bat little change in skeletal muscle or renal Mg in a study in which renal Ca fell with age (Mori & Duruisseau, 1960). In another study in which renal Ca rose substantially with age, renal Mg fell (Baskin et al, 1981). Magnesium retention has been shown to decrease in senescent mice (Draper, 1964).
The intakes of most nutrients by the elderly decline strikingly, especially in the seventh decade; the greatest decreases in the macronutrients are in fat and protein, with only small carbohydrate decreases (Exton-Smith, 1970; Crapo, 1982). Decreased physical activity is correlated with reduced energy requirements of old age (McGandy et al, 1978). Protein needs, however, rise with increasing age (Munro & Young, 1978; Uauy et al, 1978), which makes the carbohydrate intake disproportionately high. Each of these nutrients affect the Mg requirements as do several of the vitamins — low levels and poor utilization of which have been found in the elderly (Oldham, 1962, Baker et al, 1979; 1980).
Fat. Interference with Mg absorption by high intakes of saturated fat was demonstrated long ago (Sawyer et al, 1918); high intestinal fat has contributed to hypomagnesemia and resultant arrhythmia in patients with steatorrhea (Chadda et al, 1973). Fats of different chain length and degrees of saturation affect Mg absorption differently (Rayssiguier, 1981). Experimental studies of the effects of Mg on plasma lipids have yielded conflicting results, depending on the dietary mix and the species used. Early rat studies showed that Mg supplements exert a greater protective effect against fat deposition (in heart and arteries) than against hyperlipidemia and lowered lipoproteins more than liproproteins (Vitale et al., 1966; Hellerstein et al., 1960). A more recent study has shown that rats fed a Mg deficient diet that was rich in fat developed hypertriglyceridemia and significantly lower levels of high density lipid cholesterol (HDL-C) (Figure 3, Geux and Rayssiguier, 1981). The cholesterol-rich diet did not alter serum Mg levels appreciably. Pigs fed a diet low in Mg developed elevated serum triglycerides (Nuoranne et a]., 198O) Young women, who lost an average of 63 mg/day of Mg while on a diet providing 4.2-5.4 mg/kg/day (the RDA), showed rising blood lipids even though the dietary fat was low: 1 g/day (Irwin and Feeley, 1967). The authors recommended increasing the RDA for Mg.
Even though serum Mg levels do not correlate reliably with lipid levels in patients with atherosclerosis + hyperlipidemia, Mg treatment of patients with myocardial infarction has been reported to lower the LDL-C, to raise the HDL-C, and to produce clinical improvement (Seelig, 1980: chapter 5; Rayssiguier, 1981).
Sugar. High sugar intakes directly increase urinary excretion of Mg (Lindeman et al, 1967; Lennon et al., 1974). Perhaps the Mg loss caused by sugar contributed to the hypertriglyceridemia of Mg deficient rats fed a high sucrose diet that was not rich in fat (Figure 4: Rayssiguier, 1981). Diets disproportionately high in carbohydrate increase thiamim needs, which can increase Mg requirements (Infra vide).
Protein. Unduly low protein intakes have been shown to cause negative Mg balances in adolescent boys (Schwartz et a]., 1973), and in young adults (Hunt and Schofield, 1969; McCance et al, 1942); increased protein intake improved the retention of Mg. However, protein loading has increased Mg loss (Lindeman et al., 1976/1980). Of importance for the elderly whose financial status often precludes increasing protein intakes substantially, is the finding that supplementing low to marginal protein diets with Mg (increasing the Mg to optimal or above) improved the retention of nitrogen of young people (McCance et al, 1942; Schwartz et al., 1973).
Thiamin. Mg deficiency interferes with responsiveness to thiamin in rats (Itokawa et al., 1974; Zieve et al, 1968). Correction of the Mg deficit has restored thiamin responsiveness in alcoholics with encephalopathy (Stendig-Lindberg, 1972). The Mg-dependence of thiamin utilization is a consequence of the role of Mg as a cofactor in enzymes requiring thiamin (Vallee, 1960). Additionally, evidence has been presented that Mg plays a role in binding thiamin with tissue protein (Itokawa et al, 1974). Thiamin deficiency also inhibits Mg utilization. It may be clinically important that Mg deficient rats with normal thiamin intake had lower plasma and tissue Mg levels than did those with double deficiency. (Figure 5, Itokawa, 1972).
It seems plausible that efforts to repair the B1. deficiency in aged patients with or without alcoholism carry the risk, not only of a poor response to thiamin, but of intensifying Mg deficiency. The studies that show more vulnerability to thiamin deficiency in older than young subjects, and a need for higher intakes to correct the inadequacy (Oldham, 1962) did not provide data on the status of Mg. Studies of the effect of Mg supplements on the response of patients with vitamin B1. deficiency are needed.
Pyridoxine. In early Mg deficiency studies, it was found that a pyridoxine deficiency (sometimes with riboflavin deficiency) resulted in more rapid induction of the acute Mg deficiency syndrome (Greenberg, 1939). Experimental B6 deficiency causes loss of tissue Mg (Aikawa 1960), and has been associated with transitory hypermagnesemia (Durlach, 1969), perhaps with egress of Mg from tissues, and hypomagnesemia (Rigo et al, 1967), when tissue Mg is depleted. Several of the enzymes that require pyridoxal phosphate also require Mg as a cofactor (Vallee, 1960). The similarity of syndromes of experimental B6 and Mg deficiencies, and in the clinical disorders resulting from their deficiencies (Seelig, 1981) are thus not surprising. Included. among disturbances in which both Mg and B6 deficiencies might play a role that are common in the aged are chronic anemia and calcium urolithiasis. B6 dependent anemia (Frimpter et al, 1969) might also be dependent on Mg, as Mg deficiency has been shown to cause damage to erythrocyte membranes (Elin, 1973, 1976/1980). B6 and Mg have been useful alone and in combination with calcium urolithiasis (Gershoff and Prien, 1967; Johansson et al, 1982). Requiring further study is the possibility that Mg might prove useful in B6-dependent disorders in which Mg-dependent enzymes are involved. Among explanations of B6 deficiency in the aged, and the occasional failure to return to normal after trytophan-loading, is defective phosphorylation of the vitamin by pyridoxal phosphokinase to its active form (Hamfelt, 1964). This is one of the enzymes that requires Mg. Correction of pyridoxine deficiency should thus entail correction of Mg deficiency (Table 2).
Interrelationships of zinc (Zn) with B6 and Mg are also important. B deficiency causes loss of tissue Zn (Hsu, 1965), as well as Mg. Both Mg and Zn are needed for nucleic acid synthesis and for the activity of many enzymes (Parisi and Vallee, 1969). Zn is necessary for energy-linked Mg accumulation by heart mitochondria (Brierley et al, 1967).
Vitamin E. Free radical damage to membranes and to immune surveillance is implicated in the aging process (Harman et al, 1977); both vitamin E as a free radical scavenger, and Mg (Elin, 1976/1981) are important in maintaining membrane stability. Interrelationships between the two are indicated by the lowered tissue Mg levels in vitamin E deficient animals (Blaxter and Wood, 1952) and manifestations of Mg deficiency in vitamin E deficiency in rats (Schwartz, 1962). It would be interesting to ascertain whether Mg administration can protect against the free radical induced membrane damage associated with lipid peroxides, and whether the postulated slowing of the aging process by anti-oxidants (Tappel, 1968) might be potentiated by Mg.
Vitamin D and Calcium. Experimental Mg deficiency interferes with the utilization of vitamin D (Lifshitz et al, 1967a), and vitamin D deficiency results in decreased absorption of Mg and low serum Mg (Miller et al, 1964). Clinical rickets has been associated with hypomagnesemia (Breton et al, 1961). Correction of Mg deficiency has corrected vitamin D refractoriness in children (Rosler and Rabinowitz, 1973; Reddy and Sivakumar, 1974) and adults (Medalle et al, 1976). On the other hand, excess vitamin D has intensified Mg deficiency in animals (Lifshitz et al, l976b) and in clinical primary hypomagnesemia (Paunier et al, 1968). Vitamin D hyperreactivity causes hypercalcemia (Seelig, 1969), and high dietary Ca/Mg has been implicated in cardiovascular disease (Karppanen et al, 1978). In the geriatric population, vitamin D deficiency and hypocalcemia is more likely. Mg deficiency can contribute to both by decreasing target organ responsiveness (Wallach, 1976/1981).
Fiber and Phytates Americans have been advised to increase their intake of fiber because the incidence of several chronic diseases is lower among population groups on a high fiber diet than among those eating refined diets (U.S. Senate Comm., 1978). Not generally realized is the interference by phytates with the absorption of Mg (Seelig, 1981). Studies with natural fiber-rich foods, or with artificial bulk substances added to the diet, have shown production or increase of negative balance (Reinhold et al, 1976; Slavin and Marlett, 1980). Elderly people commonly use phytate or other bulk preparations to relieve their constipation. Their use, and the abuse of purgatives other than Mg salts, may well interfere with Mg utilization.
Among the changes prevalent in the old are some that resemble abnormalities that are caused by Mg deficiency, alone or in. combination with other modalities. Diseases to which the elderly are vulnerable, and some of the drugs used in therapy, contribute to Mg loss. Although the evidence is insufficient to conclude that increasing Mg intake throughout life might delay changes in senescence, it is worth investigating whether prophylactic and therapeutic use of Mg might be beneficial.
Cardiovascular disorders are the major causes of morbidity and mortality in the population over 55. There is considerable evidence that long-term Mg inadequacy, of degrees not reflected by serum Mg levels considered subnormal, can contribute to functional and structural cardiovascular disease (Seelig, 1978, 1980; Seelig and Heggtveit, 1974; Seelig and Haddy, 1976/1981). Mg, rather than Ca, has been clearly demonstrated to be the critical protective water-factor in epidemiologic studies of the different cardiac mortality rates in hard and soft water areas (Anderson et al, 1975; Neri and Marier, 1977/1982). Magnesium deficiency or loss seems central to cardiovasomyopathy (Seelig, 1980: pages 135-264).
Coronary and peripheral vasospastic diseases have been attributed to high dietary (Karppanen et al, 1978) and blood and tissue Ca/Mg ratios (Altura et al, 1981; Altura, 1982). Numerous in vitro studies have shown- the importance of Mg in regulating contractility of arterial smooth muscle, including coronary and cerebral arteries (Altura and Altura, 1980; 1981; Altura, 1982). Hormone and neurotransmitter-induced vasoconstriction, that is mediated by increased Ca, is inhibited by increased Mg. Lowering Mg concentration allows for more Ca uptake by blood vessels; raising Mg levels to above the usual serum concentration decreases the Ca influx. Mg, thus, is a natural “calcium blocker". It potentiates pharmacologic Ca-blocking effects on arteries (Altura, 1982; Turlapaty et al, 1981) and has been found to have greater anti-spasmotic activity than Verapamil in canine coronaries (Altura, p.c.).
Those with congestive heart failure and arrhythmia can lose Mg as a result of hypoxia — which causes Mg egress from tissues, including the myocardium (Hochrein et al, 1967; Seelig, 1972; 1980, p. 193). This has been shown in hearts from animals with occluded coronaries (Cummings, 1960; Jennings and Shen, 1972). Since cardiotonics stimulate Ca-inflow and Mg-outflow from the heart, and inhibit Mg-dependent mitochondrial enzymes (Seelig, 1972), it is not surprising that Mg deficiency and Ca treatment intensify digitalis toxicity, whereas Mg treatment counteracts it (review: Seelig, 1980, pp 255-259). The long-term use of diuretics in cardiac or hypertensive patients, and in those being treated for calcific urolithiasis, is the major drug-induced cause of Mg loss (Wacker, 1980). Potassium loss is always sought and treated in diuretic-treated patients; Mg loss is less often considered. Such patients are prone to K-refractory hypokalemia, sometimes with ectopic or premature ventricular contractions, that are associated with decreased muscle K and Mg levels, and that respond better when Mg is repleted than when K alone is given. (Dyckner, 1980; Dyckner and Wester, 1981).
Transient ischemic attacks, that increase in prevalence with increasing age, are associated with increased platelet aggregation and thromboembolic events. There is in vitro evidence that high concentrations of Mg inhibit platelet aggregation and release (reviews: Elin, 1976/1981, Durlach, 1976/1981), and in vivo evidence that Mg administration before temporary arterial occlusion prevents platelet deposition on the injured endothelium (Adams and Mitchell, 1979).
The protective effect of Mg was demonstrated in another study, in which arterial thickening, due to fibrosis and smooth muscle proliferation, was more marked in vessels of Mg deficient rats than in controls (Rayssiguier, 1981).
Among the cardiovasopathic models that are protected against by Mg, are the modified high fat diets that are thrombogenic (Szelenyi et al, 1967; Savoie, l972a; Savoie and DeLorme, 1976/1981). In these studies, not only were lipid blood levels increased, but Mg levels were decreased. Mg has been effective in reducing the hypercoagulability of rats and dogs on thrombogenic diets (Szelenyi et al, 1967; Savoie, l972b).
The increased incidence of thromboembolic events in women taking estrogen-containing oral contraceptives has been biased on the estrogen-lowering of plasma Mg (Goldsmith and Goldsmith, 1976/1981; Goldsmith and Johnston, 1976/1981). Patients with latent tetany of marginal Mg deficiency have exhibited phlebothrombosis (Durlach, 1967; Seelig et al, 1976/1981). The data slowing Mg reduction of arteriospasm and of platelet aggregation seem directly applicable to transient ischemic cerebral and cardiac attacks; the data on Mg-protection against arterial and cardiac damage seem relevant to the arteriosclerosis and ischemic heart disease.
Diabetes mellitus, which contributes to hyperlipidemia and cardiovascular disease, and has been termed a model for aging (Eckel and Hoefeldt, 1982), has long been known to be associated with Mg loss (Martin et al, 1952; Jackson and Maier, 1968). A decline in glucose tolerance is characteristic of aging. It has been reported in Mg deficient rats (Rayssiguier, 1981). Insulin refractoriness has improved with Mg therapy (Mules and McMullen, 1982; Seelig, unpublished data). Diabetic retinopathy has been correlated with hypomagnesemia (McNair et al, 1978), and with increased platelet aggregation (Heath et al, 1971). Since Mg inhibits platelet aggregation, its administration to diabetics is worth trying.
Collagen becomes more abundant, as well as more rigid, with increasing age (Hall, 1969). Among the nutrients that influence the metabolism of collagen are vitamins B6 and E, which have interrelationships with Mg (supra vide). Mg deficiency increases the cardiac fibrosis that is caused by noise stress-induced catecholamine release (Gunther, 1981; Ising et al, 1981). The arterial fibrosis and the delayed uterine involution and fibrosis of Mg deficiency, has been attributed to the slowing of collagen turnover (Larvor, 1981; Rayssiguier, 1981).
Stress factors particularly likely to be encountered by the aged include chronic anxiety and worry, and the acute stress of bereavement. Regardless of the cause, stress increases catecholamine and corticoid release, which in turn cause Mg loss. Catecholamines also increase myocardial Ca uptake (Nayler, 1967). Since low Mg/Ca ratios increase catecholamine secretion (Baker and Rink, 1975), a vicious cycle is thus established when Mg deficiency preexists. Well accepted is the contributory role of stress to cardiovascular disease, including sudden unexpected cardiac death. Less well known is the role of Mg loss in the damage caused by stress (Figure 7). Long-term suboptimal Mg intake, to which adaptation had taken place, so that signs of deficiency that were present early no longer existed, resulted in decreased tolerance of stress and shortened life expectancy (Heroux et al, 1973).
With advancing age there are abnormalities in immune regulation, most of which involve altered T-cell function, such as lowered resistance to intracellular microbes, increased levels of autoantibodies, and reduced immunosurveillance; i.e., against neoplasm (Makinodan and Yunis, 1980). It is thus provocative that Mg deficiency has been implicated in T-cell abnormalities and in impaired protein synthesis (reviews: Seelig, 1979; 1980/1983). Young rats with acute Mg deficiency developed lymphoid and splenic hypertrophy (Hungerford and Karson, 1960), despite significant reduction of protein synthesis by spleen and thymus, little effect on RNA synthesis, but markedly increased splenic and thymic lymphocyte DNA synthesis (Zieve et al, 1977). The lowered lymphatic protein synthesis was correlated with impaired immune response of Mg deficient rats; the increase in DNA synthesis was considered representative of an early 1ymphoproliferative process leading to neoplasia, as has been reported by others (Jasmin, 1963; Hass et al, 1976/1981). It is interesting that the neoplasms were seen only in rats deficient in Mg from early life, not in those made deficient when mature. The lymphoma-producing diets were very high in Ca, with Ca/Mg ratios of 140/1; diets that resulted in thymic hyperplasis, but not thymoma provided a ratio of 10/1 (Alcock et al, 1973). Very high Ca levels stimulate DNA synthesis and mitosis of cultured human lymphocytes (review: Seelig, 1979).
Mg deficiency suppresses levels of most immunoglobulins in rats and mice: IgG and IgA transiently, and antisheep red cell hemolysin substantially (Larvor, 76/81; Alcock and Shils, 1974; Elin, 1975; McCoy and Kenney, 1975). In contrast, IgE levels rose 3-4 fold (Prouvost-Danon et al, 1975). Fewer antibody-forming cells and markedly less rosette formation by lymphocytes of Mg deficient mice suggest the dependence on Mg by helper T-cells and the impairment of T and B cell cooperation in Mg deficiency (Guenounou et al, 1978).
Mg’ s interrelationship with other nutrients that affect immunocompetence and immunosurveillance (reviews: Seelig, 979; 1980/1983), such as interactions among Mg, Zn and B6, might influence reactions of the aged. Interrelationships among agents that protect membrane stability, such as Mg, vitamin E, Zn, and selenium might protect against oncogenesis. It must be cautioned that Mg supplementation of patients with cancer is not recommended, in view of the evidence that Mg depletion has inhibited the growth of experimental and clinical advanced neoplasm Young and Parson, 1977).
Infectious diseases cause about a third of all death in the aged, particularly those involving the urinary tract, endocardium, lungs and skin (Mostow, 1982). Impaired host defenses make the facultative pathogens a particular risk. Such microbes often require treatment, with antibiotics such as the tetracyclines and, aminoglycosides — both of which classes of drugs cause Mg loss. The tetracyclines chelate Mg (Shils, 1962); the aminoglycosides increase renal excretion of Mg as a result of the tubular damage (Keating et al, 1977).
To what extent intakes of Mg, insufficient to meet the special needs of the aged, can increase susceptibility to disorders with manifestations comparable to those produced by Mg deficiency requires study. Complicating such studies will be the many factors that affect Mg requirements, and that are a particular problem in the elderly. In considering intervention studies that might lead to improved quality and possibly length of life, methods to evaluate long-term Mg supplementation should be developed. Serum Mg determinations are unlikely to yield revealing data, usually only profound deficiencies causing hypomagnesemia. Percentage retention of parenterally administered Mg is more rewarding, but it is not appropriate for large-scale screening tests. Simplified means to measure cellular Mg: i.e. in white blood cells are under study (Ross et al, 1976/1981; 1982; Elin and Johnson, 1981; Ryan et al, 1981).
Other parameters, that should provide useful data on Mg-induced changes, include changes in HDL-C/LDL-C ratios. Electrocardiographic monitoring of patients on diuretics for correction of occult EGG changes, in association with Mg-correction of refractory hypokalemia, and in those whose arrhythmias do not respond to K repletion, should be employed in high risk patients.
Important clues to the poor adaptation to stress of the aged, might derive from extension of the important study that showed that young rats with Mg deficiency, adapted to sustained low Mg intake and ceased showing signs of deficiency (Heroux et al, 1973). The tolerance of stress by surviving old Mg deficient rats was significantly less than was that of control rats — in terms of cardiac necrosis and survival. (Figure 8). Also, their lives were shorter, even without stress.
It is not uncommon for infants with hypocalcemic convulsions, such as those shown to respond better to Mg therapy than to Ca or to barbiturates (Review: Seelig, 1978), to be treated with only Ca, Mg levels never having been obtained. Also, patients with manifestations of Mg deficiency and recorded low Mg levels (i.e with alcoholism, cardiac disease, or recovering from surgery) have been treated conventionally, without Mg repletion. Adaptation to low Mg may explain the clinical tolerance of failing to correct Mg deficiency. Long-term follow-up of patients at risk, with and without Mg repletion, should yield important information. Intervention studies in older populations, selecting groups at risk of disorders to which Mg deficiency might be contributory: hypertensives or cardiacs receiving diuretics, those with family histories of IHD, and patients with diabetes mellitus, might provide clues more quickly.
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